Gene therapy of leukemia has been studied for many years (see, for example, Holt J. T. and two others, Molecular Cellular Biology, 8(2), pp. 963-973 (1988) or Bettinger T., Read M. L., Current Opinion in Molecular Therapeutics, 3(8), pp. 116-124 (2001)). Clinical study has also been actually initiated (see, for example, Verzeletti S. and six others, Human Gene Therapy, 9(15), pp. 2243-2251 (1998) or Wierda W. G., Kipps T. J., Seminars in Oncology, 27(5), pp. 502-511 (2000)). Further, RNA-based therapeutic techniques using antisense techniques and ribozyme techniques also have been under development (see, for example, Gewirtz A. M. and two others, Blood, 92(3), pp. 712-736 (1998)).
On the one hand, RNA interference (RNAi) in Caenorhabditis elegans reported in 1998 has attracted attention as a phenomenon of inhibiting gene expression by occurrence of sequence-specific mRNA degradation with double-stranded RNA (see, for example, Fire A. and five others, Nature, 391, pp. 806-811 (1998)). The above-mentioned RNA interference is considered to occur by a mechanism wherein long double-stranded RNA is cleaved into short RNA of 21 to 25 nucleotides called siRNA (short interfering RNA) by RNase III type activity called Dicer, and then the siRNA forms a ribonucleic acid/protein complex called RISC (RNA-induced silencing complex) and binds, in an ATP-dependent manner, to a target RNA, thereby degrading the target RNA (see, for example, Bernstein E. and three others, Nature, 409(6818), pp. 363-366 (2001), Tuschit and four others, Genes and Development, 13(24), pp. 3191-3197 (1999), Zamore P. D. and three others, Cell, 101(1), pp. 25-33 (2000), Nykanen A. and two others, Cell, 107(3), pp. 309-321 (2001), Elbashir S. M. and two others, Genes and Development, 15(2), pp. 188-200 (2001), and Lipardi C. and two others, Cell, 107(3), pp. 297-307 (2001)). Thereafter, it has been reported that the RNA interference can also be applied to mammalian cells to inhibit gene expression (see, for example, Elbashir S. M. and five others, Nature, 411(6836), pp. 494-498 (2001) or Caplen N. J. and four others, Proc Natl Acad Sci USA, 98(17), pp. 9742-9747 (2001)), and RNA interfering agents inhibiting expression of a chimera mRNA unique to leukemia, such as BCR-ABL and AML1-MTG8 have been reported (see, for example, Wilda M. and three others, Oncogene, 21(37), pp. 5716-5724 (2002) or Heidenreich O. and seven others, Blood, 101(8), pp. 3157-3163 (2003)).
On the one hand, it is reported that, in leukemic cells, high expression of Flt3 which is 1000 to 10000 times higher than that in normal myeloid cells is observed in 70 to 100% of AML (acute myeloid leukemia), ALL (acute lymphocytic leukemia), CML (chronic myeloid leukemia) and the like (see, for example, Drexler H. G., Leukemia, 10(4), pp. 588-599 (1996)). Further, tandem duplication mutation (Flt3/ITD mutation, ITD: internal tandem duplication) is found in a juxtamembrane region encoding a region just below a transmembrane region of Flt3, is detected in 20 to 30% of AML, 20% of APL (acute promyelocytic leukemia, which is referred to as AML:M3 in the present FAB classification) and 5% of MDS (myelodysplastic syndrome), and is suggested to be possibly an independent factor of pathosis or poor prognosis (see, for example, International Publication No. 00/11470 pamphlet, or Nakao M. and eight others, Leukemia, 10(21), pp. 1911-1918 (1996), Yokota S. and ten others, Leukemia, 11(10), pp. 1605-1609 (1997), Kiyoi H. and nineteen others, Leukemia, 11(9), pp. 1447-1452 (1997) and Gilliland D. G., Griffin J. D., Blood, 100(5), pp. 1532-1542 (2002)). Where the Flt3/ITD mutation occurs, there occurs ligand-independent kinase activation. As low-molecular-weight compounds inhibiting such Flt3 kinase activity, for example, CEP-701 (see, for example, Levis M. and nine others, Blood, 99(11), pp. 3885-3891 (2002)), SU11248 (see, for example, O'Farrell A. M. and fourteen others, Blood, 101(9), pp. 3597-3605 (2003)), SU5416 (see, for example, Giles F. J. and sixteen others, Blood, 102(3), pp. 795-801 (2003)), AG1295 (see, for example, Levis M. and four others, Blood, 98(3), pp. 885-887 (2001)) and the like have been studied, but no compound effective as a pharmaceutical preparation has been obtained at present.